Structure Based Protein Design
Structure based protein design represents rational design approaches that are based on modeling techniques to identify/design the functionalities of the proteins. This type of method considers the tertiary/non-covalent interactions in proteins, while the sequence-based methods do not. Several methods have been developed in this category for computational design of protein structures and can be categorized into four classes: i) Homology modeling; ii) Fragment based methods; iii) Protein threading; and iv) Ab initio methods.
The principle of homology modeling relies on the homology of protein sequences, with the basic assumption that the proteins having the same sequence will end in same structural folding. Therefore, this strategy requires identification/selection of a template protein with an available 3D structure. When the template of the full-length protein is not available or the known 3D structure is of low sequence similarity, fragment based methods or protein threading comes in helpful. Fragment based methods are based on protein structure database while the target protein is only known as fragments. Meanwhile, protein threading is the only method of choice where no reliable homologue structure and fragments are available. Ab initio is a special approach with all-atom simulation using potential functions. The method does not require any structural information/protein database as the template.
Following computational design, experimental validation is carried out through methods such as peptide synthesis and site-directed mutagenesis, or artificial gene synthesis with unnatural base pair (UBP) involved.
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1. Gulati, K., Poluri, K.M. (2016) An overview of computational and experimental methods for designing novel proteins. Recent Patents on Biotechnology. 10: 235-263.
Figure 1 Structure based computational approaches for designing and identifying different protein folds.
(Recent Patents on Biotechnology 2016)